Immunomodulators such as BCG and the interferons display a strong anti-tumoral activity in bladder cancer, but the mechanisms mediating tumor cell sensitivity or resistance to these therapies remain unclear. Members of a family of cell surface receptors homologous to the type I TNF family and Fas are commonly activated by immunomodulators and cancer chemotherapeutic agents in other solid tumors. Our preliminary data demonstrate that variants of a human bladder TCC cell line orthotypically selected for enhanced tumorigenicity are completely resistant to interferon- and death receptor-induced apoptosis, although they are equally sensitive to induction of apoptosis by a variety of pharmacological death stimuli. Our overall hypothesis is that receptors mediate the anti-tumor effects of the interferons in bladder cancer and that acquisition of death of receptors mediate the anti-tumoral effects of the interferons in bladder cancer and that acquisition of death of receptors mediate the anti-tumoral effects of the interferons in bladder cancer and that acquisition of death of orthotypically-selected cell variants, in our preclinical orthotopic nude mouse model of human bladder cancer, and in a Phase clinical trial that will provide use with primary tissue specimens before and immediately after IFN therapy. Our Specific Aims are, (1) to define the molecular mechanisms involved in cytokine resistance in vitro, (2) To define the role of death receptors in tumor progression and the response to IFN-based therapy in vivo, and (3) To determine the role of death receptors in the response to IFN-based combination chemotherapy in patients with locally invasive bladder cancer. Significant improvements to current therapeutic strategies are dependent on a better understanding of tumor cell biology. Our studies will allow us to test a widely6-held scientific hypothesis in a unique preclinical models and in bladder cancer patients. We expect that the information gained from these studies will not only allow for better stratification of patients to particular existing regiments but also to the design of novel, rational, death receptor-based future strategies.